Over the past two decades, an increased prevalence of sleep deprivation in the US has become a major public health challenge. Sleep deprivation been implicated in the epidemic of the metabolic syndrome, a condition characterized by insulin resistance, hyperlipidemia, cardiovascular disease and hypertension. Presently, 30% of the US population is overweight or obese and diabetes affects nearly 17% of persons over the age of 65. Recent clinical research indicates that sleep deprivation may pose a risk for the development of diabetes and the metabolic syndrome, however the underlying physiological and pathophysiological basis for the connection between sleep and metabolic homeostasis remains incompletely understood. This application proposes to exploit a novel experimental model of acute and chronic partial sleep deprivation in order to dissect the link between sleep loss and the metabolic syndrome. Already, we have found that chronic partial sleep loss in our animal model reproduces features of the metabolic syndrome including changes in hypothalamo-adrenal axis, decreased leptin and increased fatty acids. We have also made exciting discovery that suggest a role for alterations in the biological clock and clock regulated metabolic pathways that may lead to the metabolic syndrome. We now propose to apply the model we have developed together with molecular genetic tools to investigate the basic mechanisms that link sleep, circadian rhythms, food intake and energy homeostasis. Insight gained from these studies will provide new strategies to prevent metabolic complications associated with sleep deprivation and uncover novel metabolic targets for treatment of obesity and its co-morbidities.